Increasing Ischemic Myocardial Tissue Perfusion by Mechanical LV Support

通过机械左心室支持增加缺血性心肌组织灌注

基本信息

项目摘要

PROJECT ABSTRACT/SUMMARY Emerging evidence suggests a possible limitation of myocardial infarction (MI) size by acute mechanical left ventricular (LV) support. A phase II clinical trial of mechanical LV unloading for acute MI has begun enrolling after the recent completion of the Door-to-Unloading (DTU) STEMI Trial, which demonstrated both safety and feasibility of this approach. This is an exciting area of medicine, where no new therapy has become clinically routine for salvaging ischemic myocardium in MI after establishing coronary reperfusion. Despite the strong enthusiasm and repeatedly shown efficacy in animal experiments, limited knowledge exists on how it limits infarct size. This proposal focuses on understanding the physiological effects of mechanical LV support in acute MI and its mechanisms of infarct size reduction. Our preliminary data suggests that mechanical LV support increases ischemic myocardial tissue flow and perfusion by lowering LV diastolic wall stress. Based on our data, we expect that “reduced diastolic wall stress” and “improved tissue perfusion” play the key roles in infarct size reduction during mechanical LV support, rather than generally accepted mechanism that “reduced cardiac work” limits infarct size. To examine our hypothesis, we will use large animal models of myocardial ischemia/reperfusion and study the impact of acute LV support on coronary flow. In Aim 1, we will study the relationship between diastolic LV wall stress and ischemic tissue perfusion under different LV loading conditions. Comprehensive assessment of LV pressure/volume, coronary flow, and myocardial tissue perfusion during different LV loading conditions will offer improved mechanistic understanding. In Aim 2, we will determine the factors that regulate ischemic tissue perfusion during LV support. This Aim will define patient characteristics that benefit most from mechanical LV support in acute MI. In Aim 3, molecular mechanisms of coronary flow regulation is examined by focusing on microRNA-146. We expect that decreased diastolic LV wall stress increases exosomal microRNA-146 secretion from the heart, which inhibits coronary vascular oxidative stress and improves tissue perfusion. Understanding the mechanisms of infarct size reduction is essential to improve patient selection for this novel and promising, but invasive therapy for acute MI. Results of proposed studies will help define optimal support settings, establish effective clinical protocols, and identify appropriate patient population.
项目摘要/总结 新出现的证据表明,急性机械性心肌梗死(MI)的大小可能受到限制, 左心室(LV)支持。急性心肌梗死机械左心室去负荷的II期临床试验已开始招募 在最近完成了门到卸载(DTU)STEMI试验后,该试验证明了安全性和 这种做法的可行性。这是一个令人兴奋的医学领域,在临床上还没有新的治疗方法 常规用于在建立冠状动脉再灌注后挽救MI中的缺血心肌。尽管大力 热情和动物实验中反复显示的功效,但对它如何限制梗死的知识有限 尺寸 该提案的重点是了解急性心肌梗死中机械左心室支持的生理效应 及其缩小梗死面积的机制。我们的初步数据表明,机械左心室支持 通过降低LV舒张期壁应力增加缺血心肌组织流量和灌注。根据我们的数据, 我们预期“舒张期室壁应力降低”和“组织灌注改善”在梗死面积中起关键作用。 在机械LV支持期间减少,而不是普遍接受的“减少心脏工作”的机制 限制了梗死面积。 为了验证我们的假设,我们将使用心肌缺血/再灌注的大型动物模型, 研究急性左心室支持对冠状动脉血流的影响。在目标1中,我们将研究舒张功能与 不同负荷条件下左室壁应力和缺血组织灌注。全面评估 在不同的LV负荷条件下,LV压力/容量、冠状动脉流量和心肌组织灌注的变化将 提供更好的机械理解。在目标2中,我们将确定调节缺血组织的因素 LV支持期间的灌注。该目标将定义从机械LV中获益最多的患者特征 支持急性心肌梗死。在目标3中,冠状动脉血流调节的分子机制通过关注 微小RNA-146。我们预期舒张期左室壁应力降低会增加外泌体microRNA-146的分泌, 从心脏,抑制冠状血管氧化应激和改善组织灌注。 了解梗死面积减少的机制对于改善患者选择至关重要 新的和有前途的,但侵入性治疗急性心肌梗死。拟议研究的结果将有助于确定最佳的 支持设置,建立有效的临床协议,并确定适当的患者人群。

项目成果

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Kiyotake Ishikawa其他文献

Kiyotake Ishikawa的其他文献

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{{ truncateString('Kiyotake Ishikawa', 18)}}的其他基金

Percutaneous Left Ventricular Unloading for Cardiogenic Shock: Beyond Acute Hemodynamic Support
经皮左心室减负荷治疗心源性休克:超越急性血流动力学支持
  • 批准号:
    10319941
  • 财政年份:
    2017
  • 资助金额:
    $ 70.64万
  • 项目类别:
Percutaneous Left Ventricular Unloading for Cardiogenic Shock: Beyond Acute Hemodynamic Support
经皮左心室减负荷治疗心源性休克:超越急性血流动力学支持
  • 批准号:
    10066358
  • 财政年份:
    2017
  • 资助金额:
    $ 70.64万
  • 项目类别:

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